The hepatitis C virus (HCV) is a plus-stranded RNA virus that infects more than 100 million people and causes acute and chronic hepatitis and hepatocellular carcinoma. The outcome of HCV infection is thought to be determined by the high replication and mutation rates of the virus, and by the kinetics, magnitude, quality and duration of the T cell response. In particular, many HCV-specific CD8( T cells that can be visualized with HLA class I tetramers fail to produce inteferon gamma (IFNgamma), especially during chronic infection. The potential importance of this dysfunctional phenotype in the pathogenesis of HCV infection is suggested by our recent observations that: (a) it also heralds the onset of the CD8( T cell response to HCV during the incubation phase of infection; (b) it correlates with high viral titers and significant liver cell injury during acute viral hepatitis; (c) it recovers or is replaced by CD8+ T cells that produce IFNgamma when the virus is cleared. We suggest that dynamic changes in T cell function such as this, and others that have not yet been examined, may have an important impact on the course and outcome of HCV infection. In the current application, therefore, we will test this hypothesis by comparing the phenotypic and functional evolution of the CD4( and CD8( T cell responses to HCV with the severity and duration of infection in acutely and chronically infected humans and chimpanzees. We will also perform in vivo depletion experiments to directly examine whether CD4+ or CD8+ T cells control HCV infection, and to determine the extent to which their antiviral potential is mediated by IFNgamma. This information will not only provide fundamental insight into the immunobiology of HCV infection, it may also lead to the development of immunotherapeutic and antiviral approaches to prevent and treat this serious disease.